This preprint presents a critical review and conceptual framework on the use of youth-derived exosomes as a potential therapeutic strategy for Alzheimer's disease (AD). Despite recent anti-amyloid disease-modifying approvals, no broadly effective therapy halts or reverses late-onset AD. Most development programs continue to target downstream amyloid, tau, inflammatory, or synaptic endpoints rather than aging biology itself. Preclinical work on young plasma and youth-associated extracellular vesicles has generated considerable interest in exosome-based rejuvenation. However, this evidence derives almost entirely from rodent models and immortalized cell lines, which do not fully recapitulate the epigenetic, transcriptomic, and cellular aging signatures of human neurons. As a result, it remains unclear whether the benefits seen in animals reflect genuine modulation of human neuronal aging or context-specific responses with limited translational relevance. We examine the current state of exosome research in AD and aging, and identify key translational challenges that are often underappreciated. These include exosome heterogeneity, lack of standardization, cargo complexity, and the critical distinction between pathology-modifying and aging-rejuvenating effects. We argue that the field would benefit from a deliberate shift toward human neuron-centric mechanistic studies using models that preserve intrinsic aging signatures. In particular, we highlight directly converted (induced) neurons from aged donors, complemented by isogenic iPSC-derived neurons with induced-aging approaches. Building on this, we propose a stepwise, go/no-go experimental framework for cargo deconvolution. This involves sequential perturbation of RNA, protein, and lipid components, with orthogonal validation, and integrates classical AD pathology readouts with deep aging-biology markers such as cellular senescence, epigenetic age, and mitochondrial function. By bridging the conceptual strengths of the plasma-rejuvenation paradigm with the rigor of human neuronal systems, this review aims to chart a more realistic path toward exosome-based strategies that are both mechanistically grounded and clinically relevant.
Hong et al. (Sun,) studied this question.